Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus‐specific neutralizing antibody response

EMBO Molecular Medicine

Zhisheng Her⁴  Terk-Shin Teng⁴  Jeslin JL Tan⁴  Teck-Hui Teo⁴  Yiu-Wing Kam⁴  Fok-Moon Lum⁴  Wendy WL Lee⁴  Christelle Gabriel⁴  Rossella Melchiotti⁴  Anand K Andiappan⁴  Valeria Lulla¹  Aleksei Lulla¹  Mar K Win³  Angela Chow³  Subhra K Biswas⁴  Yee-Sin Leo³  Marc Lecuit²  Andres Merits¹  Laurent Rénia⁴ 

[1] Institute of Technology, University of Tartu, Tartu, Estonia;Institut Pasteur, Biology of Infection Unit, Paris, France;Institute of Infectious Disease and Epidemiology (IIDE), Tan Tock Seng Hospital, Singapore, Singapore;Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore

关键词: Chikungunya virus;    innate immunity;    joint inflammation;    neutralizing antibodies;    TLR3;   

DOI  :  10.15252/emmm.201404459

来源: Wiley

【 摘 要 】

Abstract

RNA-sensing toll-like receptors (TLRs) mediate innate immunity and regulate anti-viral response. We show here that TLR3 regulates host immunity and the loss of TLR3 aggravates pathology in Chikungunya virus (CHIKV) infection. Susceptibility to CHIKV infection is markedly increased in human and mouse fibroblasts with defective TLR3 signaling. Up to 100-fold increase in CHIKV load was observed in Tlr3^−/− mice, alongside increased virus dissemination and pro-inflammatory myeloid cells infiltration. Infection in bone marrow chimeric mice showed that TLR3-expressing hematopoietic cells are required for effective CHIKV clearance. CHIKV-specific antibodies from Tlr3^−/− mice exhibited significantly lower in vitro neutralization capacity, due to altered virus-neutralizing epitope specificity. Finally, SNP genotyping analysis of CHIKF patients on TLR3 identified SNP rs6552950 to be associated with disease severity and CHIKV-specific neutralizing antibody response. These results demonstrate a key role for TLR3-mediated antibody response to CHIKV infection, virus replication and pathology, providing a basis for future development of immunotherapeutics in vaccine development.

Synopsis

TLR3-mediated innate response against CHIKV infection modulates the adaptive immune response and TLR3 deficiency results in enhanced viremia and more severe pathology in mice; in CHIKV-infected patients, TLR3 expression is high and a TLR3 SNP associates with disease severity.

• TLR3 regulates host immunity in CHIKV infection and pathology in humans and mice.
• A loss of TLR3 was demonstrated to markedly increase virus replication and dissemination that led to more severe joint pathology.
• Bone marrow chimeric experiments indicated that TLR3-expressing hematopoietic cells play a role CHIKV clearance.
• The loss of TLR3 impaired neutralizing capacity due to altered virus-neutralizing epitope specificity.
• SNP genotyping analysis on TLR from patients identified SNP rs6552950 as associated with disease severity.

【 授权许可】

CC BY   
© 2014 Agency for Science, Technology and Research (A*STAR). Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.